Abstract
The stress-induced p38 mitogen-activated protein kinase (MAPK) pathway plays an essential role in multiple physiological processes, including cancer. In turn, p38MAPK phosphorylation at Thr180 and Tyr182 is a key regulatory mechanism for its activation and functions. Here we show that this mechanism is actively regulated through isomerisation of Pro224. Different cyclophilins can isomerise this proline residue and modulate the ability of upstream kinases to phosphorylate Thr180 and Tyr182. In vivo mutation of Pro224 to Ile in endogenous p38MAPK significantly reduced its phosphorylation and activity. This resulted in attenuation of p38MAPK signalling, which in turn caused an enhanced apoptosis and sensitivity to a DNA-damaging drug, cisplatin. We further found a reduction in size and number of lesions in homozygous mice carrying the p38MAPK P224I substitution in a K-ras model of lung tumorigenesis. We propose that cyclophilin-dependent isomerisation of p38MAPK is an important novel mechanism in regulating p38MAPK phosphorylation and functions. Thus, inhibition of this process, including with drugs that are in clinical trials, may improve the efficacy of current anti-cancer therapeutic regimes.
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Abbreviations
- MAPK:
-
mitogen-activated protein kinases
- Thr:
-
threonine
- Tyr:
-
tyrosine
- Pro:
-
proline
- Gly:
-
glycine
- UV:
-
ultraviolet
- MK2:
-
mitogene-activated protein kinase-activated protein kinase 2
- MKK:
-
matogen-activated protein kinase kinase 3
- JNK:
-
c-Jun N-terminal kinase
- Pin1:
-
peptidyl-prolyl cis–trans isomerase NIMA-interacting 1
- Cyp:
-
cyclophilin
- SILAC:
-
stable isotope labelled amino acids in cell culture
- GFP:
-
green fluorescent protein
- RNA:
-
ribonucleic acid
- DNA:
-
deoxyribonucleic acid
- Arg:
-
arginine
- TNF:
-
tumour necrosis factor
- BrdU:
-
bromodeoxyuridine
- MEF:
-
mouse embryo fibroblasts
- Cxcl5:
-
C-X-C motif chemokine 5
- PPIase:
-
peptidyl-prolyl-cis-trans-isomerase
- NF-B:
-
nuclear factor kappa-light-chain-enhancer of activated B cells
- shRNA:
-
small hairpin ribonucleic acid
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Acknowledgements
The research of DVB was supported by the Foundation ARC (France) and for AB by A*STAR’s JCO project grant 14302FG090 (Singapore). We are grateful to Dr. Elise Courtois, Jun Siong Low, Nancy Zhao Qi and Matthias Schmitt for the assistance.
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Brichkina, A., Nguyen, N., Baskar, R. et al. Proline isomerisation as a novel regulatory mechanism for p38MAPK activation and functions. Cell Death Differ 23, 1592–1601 (2016). https://doi.org/10.1038/cdd.2016.45
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DOI: https://doi.org/10.1038/cdd.2016.45
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